Resistance of mice to infection by Listeria monocytogenes involves a biphasic response. Phase one consists of the first 48 hrs post infection, during which there is multiplication of Listeria in the liver and spleen of infected mice. In these non-immune mice, macrophages and polymorphonuclear leukocytes are the effector cells involved in controlling multiplication. In the second phase, cell-mediated immunity develops, beginning on day two, during which multiplication of Listeria is prevented by macrophages possessing increased microbicidal activity that is mediated through the action of lymphokines released by immunologically committed T-lymphocytes. This research proposal will focus on the early phase (0-48 hrs) of infection, and has two objectives: (1) To ascertain the role of natural killer (NK) cells during the early phase (0-48 hrs) of infection with Listeria. Initially the effectiveness of NK cells in natural resistance will be examined in vivo by selectively depleting normal animals of functional NK cells using NK specific antiserum. Normal and NK depleted animals will be infected with viable Listeria and monitored for in vivo clearance of microorganisms from liver and spleen at various time intervals post infection. Secondly, through the use of a specific immunopharmacological agent, animals will be depleted of Nk cells and other natural effector cells, and reconstituted with NK enriched lymphoid cells. Experimental and control animals will be infected and tissues assayed for NK activity, clearance of Listeria, and percent survival. Finally, it will be determined whether acute infection of mice with Listeria generated NK cells possessing listericidal activity. (2) To analyze the morphologicaland functional characteristics associated with Nk cells isolated from animals during the early phase of listerial infection. These studies will include (a) comparison of "activated" and endogenous NK cells with respect to cell surface phenotype and target cell specificity, (b) the identification of regulatory molecules responsible for the augmented NK activity observed in Listeria infected animals, and (c) determination of whether NK cells isolated during the early phase of microbial infection are capable of lymphokine production, specifically interferon and interleukin 2. Results from these studies will contribute to a more complete understanding of the effector cells which are involved in natural resistance to infection by microorganisms prior to the development of specific cellular immunity.